Cabergoline is an ergoline derivative with formula 1 ((6-allylergolin-8β-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. It is known for treatment of a number of diseases, including CNS disorders, reversible obstructive airways disease, prolactin inhibition, for controlling intra-ocular pressure and for treating glucoma.
A number of different forms of cabergoline are known and, by way of example, PCT patent publication no. WO 01/72747 describes form II and PCT patent publication no. WO 01/72746 describes form VII.
Preparation of cabergoline Form I is described in PCT patent publication nos. WO 01/70740, WO 03/078392 and WO 03/078433. It is known from PCT patent publication no. WO 01/70740 to prepare crystalline cabergoline form I from a solvent comprising a toluene/diethylether mixture. From PCT patent publication nos. WO 03/078392 and WO 03/078433, it is known to prepare a solvate of cabergoline and toluene, and obtain crystalline form I by drying the solvate.
It is desired, however, to prepare crystalline cabergoline of form I having high purity.
It is also desired to prepare cabergoline form I having a particle size (following crystallization) that is relatively small and which requires no or relatively little milling to obtain the particle size desired in the eventual pharmaceutical product. Milling and other such processing is undesirable as it tends to lead to conversion of pure polymorphic forms of cabergoline into polymorphic mixtures. One problem with the methods described in PCT patent publication no. WO 03/078433 and other references is that crystals of cabergoline form I are formed having a relatively large particle size.
It is also desired to provide a process for preparation of cabergoline in which conversion of the intermediate solvate to the final cabergoline form I is quick and efficient. A difficulty with known processes (e.g., those described in within PCT patent publication no. WO 03/078433) for this conversion is that protracted drying periods (i.e., in excess of 48 hours) are required to remove the solvent from the solvate.